Olaparib Approved in Japan for BRCA-Mutated, HER2-Negative, High-Risk Early Breast Cancer

Andrew Tutt, MD, PhD

The Japanese Ministry of Health, Labor, and Welfare has approved olaparib (Lynparza) as an adjuvant treatment for patients with BRCA-mutated, HER2-negative, high-risk early breast cancer.¹

The approval was based on findings from the phase 3 OlympiA trial (NCT02032823), which showed that olaparib elicited a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) vs placebo, reducing the risk of invasive recurrences, new cancers, or death by 42% (HR, 0.58; 99.5% CI, 0.41-0.82; P < .0001).²

Patients treated with olaparib also achieved a benefit in overall survival (OS) compared with placebo, with a 32% reduced risk of death (HR, 0.68; 98.5% 0.47-0.97; P = .009).

“[The approval of olaparib] marks a new era of care for patients in Japan. For patients with high-risk early-stage breast cancer, including those with germline BRCA mutations, recurrence rates remain unacceptably high, with more than one in four of these patients seeing their cancer return following surgery and systemic treatment,” Andrew Tutt, MD, PhD, the global chair of the OlympiA trial and professor of oncology at The Institute of Cancer Research and King’s College London, stated in a press release. “Today’s approval offers eligible patients in Japan an effective and targeted treatment that improves survival and helps to prevent cancer recurrence.”

In March 2022, the FDA approved olaparib for the adjuvant treatment of patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer who have previously received chemotherapy either before or after surgery.³

Previously in August 2022, the European Commission approved olaparib as a single agent or in combination with endocrine therapy for the adjuvant treatment of adult patients with germline BRCA1/2-mutated, HER2-negative, high-risk early breast cancer who have been previously treated with neoadjuvant or adjuvant chemotherapy.⁴ Both approvals were also based on data from OlympiA.

The multicenter, randomized, placebo-controlled OlympiA trial enrolled 1836 patients with histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that was either triple-negative, or estrogen receptor– or progesterone receptor–positive and HER2-negative.⁵ Patients were also required to have a documented BRCA1/2 mutation.

Other key inclusion criteria included completion of adequate breast and axilla surgery; prior treatment with at least 6 cycles of neoadjuvant or adjuvant chemotherapy; and an ECOG performance status of 0 or 1. Prior treatment with a PARP inhibitor was not permitted.

Once enrolled, patients were randomized 1:1 to 300 mg of oral olaparib twice daily for 1 year (n = 921) or placebo (n = 915). The primary end point for the study was iDFS. Secondary end points included distant disease-free survival (DDFS), OS, health-related quality of life, and safety.

Additional findings from the study showed 3-year iDFS rates of 85.9% and 77.1% in the olaparib and placebo arms, respectively (8.8% difference; 95% CI, 4.5%-13.0%). The 3-year DDFS rates were 87.5% and 80.4% in the olaparib and placebo groups, respectively (7.1% difference; 95% CI, 3.0%-11.1%; HR, 0.57; 99.5% CI, 0.39-0.83; P <.001).

Regarding safety, the most common any-grade adverse effects (AEs) in the olaparib arm were nausea (57%), fatigue (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%) and stomatitis (10%). Approximately 10% of patients in the olaparib arm discontinued treatment due to AEs. The most common grade 3 or higher AEs included anemia (9%), neutropenia (5%), leukopenia (3%) and fatigue (1.8%).

References

1. Lynparza approved in Japan as adjuvant treatment for patients with BRCA-mutated HER2-negative high-risk early breast cancer. News release. AstraZeneca. August 25, 2022. Accessed August 25, 2022. https://bit.ly/3pMbxp6
2. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215
3. Lynparza approved in the US as adjuvant treatment for patients with germline BRCA-mutated HER2-negative high-risk early breast cancer. AstraZeneca. News release. March 11, 2022. Accessed August 25, 2022. https://bit.ly/3tQePcn
4. Lynparza® (olaparib) approved in the EU as adjuvant treatment for patients with germline BRCA-mutated, HER2-negative high-risk early breast cancer. News release. Merck. August 4, 2022. Accessed August 25, 2022. https://bit.ly/3zY2mre
5. Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2 negative primary breast cancer (OlympiA). ClinicalTrials.gov. Updated June 13, 2022. Accessed August 25, 2022. https://clinicaltrials.gov/ct2/show/NCT02032823